It has been known for a long time that when traditional insulin is used to treat diabetes, it is associated with an increase in body weight. Insulin has to be injected subcutaneously up to several times per day. Thus, an antidiabetic therapeutic approach should not only lower fasting and postprandial blood glucose levels but optimally also induce weight loss. Type 2 diabetes is generally treated in the early phases with diet and exercise. As the condition progresses, various oral anti-diabetic agents are added. Novel hormone-based therapies for type 2 diabetes are now emerging resembling an endogenous mode of action, such as glucagon like peptide (GLP)-1 and amylin analogues. These agents do not only improve glucose homeostasis but also very promisingly exert beneficial effects on body weight. In obese individuals, fasting amylin concentrations are elevated in conjunction with hyperinsulinemia and in patients with type 2 diabetes, amylin, like insulin, is relatively deficient depending on the severity of β-cell secretory failure. Amylin receptor agonists are useful in reducing food intake and treating obesity. Human amylin is a 37 amino acid long polypeptide which has physico-chemical properties that make its use as a drug troublesome. In particular, it has a tendency for fibrillogenesis, i.e. the formation of fibrils, in vitro and/or ex vivo and becomes ineffective due to precipitation. Pramlintide is a drug product marketed by Amylin Pharmaceuticals as Symlin® and a human amylin analogue and receptor agonist used in the treatment of diabetes as an add-on to insulin. Pramlintide is chemically unstable at neutral pH and it is therefore provided in an acidic solution.
The calcitonin receptor is found in many tissues throughout the body and it is believed to be involved in regulation of bone metabolism. Salmon calcitonin is currently sold under the tradename Miacalcic®. The product is used against hypercalcaemia, osteoporosis (including post-menopausal osteoporosis and glucocorticoid-related osteoporosis), ostitis deformans (Pagets disease) and is administered once daily either by injection or nasally. The calcitonin is bound to specific receptors in the membrane of the skeleton, the kidneys and in the central nervous system (CNS). Calcitonin is chemically unstable at neutral pH and it is therefore provided in an acidic solution.
Polypeptides with activity at both the amylin and calcitonin receptor and the amylin receptor may be advantageous; however increased half-life of amylin and calcitonin receptor agonists would highly increase the usability and convenience for the use as a medicament in treating the above mentioned diseases. A further drawback of the currently known pool of calcitonin and amylin peptides is that they are only chemically stable in solution when handled in a narrow acidic pH range, which makes them bothersome to handle under circumstances were a broader range of pH is desired. Thus polypeptides which are amylin and/or calcitonin receptor agonists with more flexible solubility profiles would increase the usability in medicinal products.